Novel hydroxyl pyranone compound, method for producing same, and cosmetics composition comprising compound

ABSTRACT

The present invention relates to a novel hydroxyl pyranone compound, a method for producing same, and a cosmetic composition having the compound. The hydroxyl pyranone compound according to the present invention exhibits markedly improved effectiveness compared to the conventional adipocyte differentiation-promoting material, and thus is preferably included as an active ingredient in a cosmetic composition for increasing skin volume or elasticity.

TECHNICAL FIELD

The present application claims the benefit of Korean Patent ApplicationNo. 10-2015-0169638, filed on Dec. 1, 2015 with the Korean IntellectualProperty Office, the disclosure of which is herein incorporated byreference in its entirety.

The present invention relates to a novel hydroxyl pyranone compoundhaving adipocyte differentiation promoting ability, a method forpreparing the same, and a cosmetic composition containing the same as anactive ingredient.

BACKGROUND ART

The basic structure of the skin is maintained by subcutaneous adiposetissue. The subcutaneous adipose tissue plays a critical role inmaintaining the volume and strength of the skin. Accordingly, in orderto maintain and improve the volume and elasticity of the skin,increasing the volume of the adipose tissue rather than imparting theelasticity to the dermis or epidermis in the outer layer of the skin canbe a fundamental solution.

Specifically, as the aging of the human body progresses, wrinkles aregenerated on the skin, and at the same time, the elasticity of the skinis also reduced. The aging of the skin, such as wrinkle formation anddecreased elasticity, is a complex phenomenon caused by the decrease inthe activity of adipocytes or hence the decrease in lipid droplets alongwith the degradation and reduction of skin fibers such as collagen andelastin, which are skin components. Therefore, if the lipid droplets canbe produced and accumulated by promoting adipocyte differentiation inhumans, the wrinkles and elasticity of the skin can be improved.

Recently, upon reviewing various research trends using adipocytes,currently, studies using adipocytes have been actively conducted in avariety of fields including studies for increasing the volume feel andelasticity of the skin. Among them, preadipocytes are widely usedbecause they have the property of differentiating into adipocytes bydifferentiation inducers such as insulin.

Particularly, among these preadipocytes, mesenchymal stem cells foradipocytes have recently received attention. Since adipose-derivedmesenchymal stem cells can be differentiated using methods similar tothose used to differentiate preadipocytes into adipocytes (Exp. CellRes. 2006, 312, 1856-1864), they are widely used in the study ofadipocyte differentiation (Science 1999, 284, 143-146). In addition,such adipose-derived mesenchymal stem cells are known to be able todifferentiate not only into adipocytes but also into other types ofcells such as chondrocytes and bone cells (J. Cell Sci. 2006, 119,2204-2213), and are distributed in most tissues of the body, and thusare thought to be infinitely useful.

In the meantime, various attempts have been made to promote thedifferentiation of adipocytes in order to improve the volume andelasticity of the skin. According to the results of such previousstudies, it has been reported that cinnamic acid compounds showadipocyte differentiation promoting effect. In addition, there has beena report that hydroxyl pyranone derivatives including cinnamic acidmother nucleus significantly increase adipocyte differentiationpromoting effect compared to cinnamic acid. In this regard, it wasconfirmed that as a result of analyzing the structural activecorrelations of various derivatives, the double bond of cinnamic acidplays an important role.

However, since the effect of increasing the volume and elasticity of theskin in the human body, when incorporating these materials for promotingadipocyte differentiation into actual cosmetic compositions, etc. wasstill insufficient, it has been difficult for consumers to obtainmaximum satisfaction related to the use of cosmetic composition.

Accordingly, it was necessary to develop a material for promotingadipocyte differentiation with improved efficacy.

[Prior Art]

Hydroxy pyranone derivative and preparation method thereof (Korea PatentNo. 10-0482668)

DISCLOSURE Technical Problem

In order to solve the above-described problems, the inventors of thepresent invention have conducted various studies on the compoundscapable of improving the adipocyte differentiation promoting effect overthe existing compounds based on the above-mentioned previous researchresults. As a result, the inventors have completed the present inventionby preparing a novel compound comprising a mother nucleus of3-(2,6,6-timethyl-cyclohex-1-enyl)-propenoic acid among the hydroxylpyranone compounds, and then confirming that the novel compound improvesthe differentiation promoting effect of adipocytes.

Therefore, it is an object of the present invention to provide a novelhydroxyl pyranone compound which improves the differentiation promotingeffect of adipocytes.

In addition, it is another object of the present invention to provide amethod for preparing the novel hydroxyl pyranone compound.

In addition, it is still another object of the present invention toprovide a cosmetic composition comprising the novel hydroxyl pyranonecompound as an active ingredient.

Technical Solution

According to an object of the present invention, the present inventionprovides a hydroxyl pyranone compound represented by the followingFormula 1:

According to another object of the present invention, the presentinvention provides a method for preparing a hydroxyl pyranone compoundof Formula 1 by reacting a compound of the following Formula 2 and acompound of the following Formula 3, which is represented by thefollowing Reaction Scheme 1:

wherein X and M are as described in the specification.

According to still another object of the present invention, the presentinvention provides a cosmetic composition comprising a hydroxyl pyranonecompound represented by Formula 1 as an active ingredient.

Advantageous Effects

The hydroxyl pyranone compound according to the present invention has anenhanced adipocyte differentiation promoting effect compared to theconventional seletinoid G or other adipocyte differentiation promotingcompounds.

Specifically, since the compounds of the present invention can promotethe phenomenon of differentiation of human mesenchymal stem cells intoadipocytes and thus induce lipid droplets, thereby enhancing the volumeand elasticity of the skin, it can be formulated into various cosmeticproducts to improve the satisfaction of consumers.

BEST MODE

Hereinafter, the present invention will be described in detail.

The present invention provides a novel hydroxyl pyranone compoundrepresented by the following Formula 1:

The IUPAC name of the hydroxyl pyranone compound of Formula 1 is3-(2,6,6-trimethyl-cyclohex-1-enyl)-propenoic acid5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester.

The compound of Formula 1 is an off-white solid compound at roomtemperature.

The hydroxyl pyranone compounds according to the present invention mayinclude isomers. At this time, the “isomers” particularly may includeoptical isomers (e.g., essentially pure enantiomers, essentially purediastereomers, or mixtures thereof), as well as conformation isomers(i.e., isomers differing only in the angle of one or more chemicalbonds), position isomers (particularly tautomers) or geometric isomers(e.g., cis-trans isomers).

The compound represented by Formula 1 is prepared by reacting a pyranonecompoundof Formula 2 and a cyclohexenyl ester compoundof Formula 3 asshown in the following Reaction Scheme 1:

wherein X is a halogen element and M is Li, Na or K.

Referring to Reaction Scheme 1, the compound of Formula 1 is prepared bya coupling reaction between a halogen element in the pyranone compoundand a metal in the cyclohexenyl ester compound.

Herein, X in the pyranone compound of Formula 2 is a halogen element. Atthis time, the halogen element may be F, Cl, Br, or I, preferably Cl.The compound of Formula 2 is commercially available or can be prepareddirectly.

In the Example of the present invention,5-hydroxy-2-(chloromethyl)-4H-pyran-4-one in which X is Cl was used,which was prepared directly by reacting5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one with thionyl chloride(SOCl₂).

In addition, the cyclohexenyl ester compound of Formula 3 is present ina form in which a cation (M⁺) is bonded to the carboxyl group of3-(2,6,6-timethyl-cyclohex-1-enyl)-propenoic acid, which is an ionizedsalt form of 3-(2,6,6-timethyl-cyclohex-1-enyl)-propenoic acid.

The cation (M⁺) may be any one selected from the group consisting ofLi⁺, Na⁺, and K⁺. Preferably, the compound may be an ion-bindingcompound of 3-(2,6,6-timethyl-cyclohex-1-enyl)-propenoic acid and Na⁺,and it may be prepared by dissolving3-(2,6,6-timethyl-cyclohex-1-enyl)-propenoic acid and sodium hydroxidein methanol and ionizing them and then distilling methanol.

In a preferred embodiment of the present invention, the hydroxylpyranone compound of Formula 1 was prepared through an ester linkage of5-hydroxy-2-(chloromethyl)-4H-pyran-4-one as the compound of Formula 2and sodium 3-(2,6,6-timethyl-cyclohex-1-enyl)-propenoate as the compoundof Formula 3.

At this time, the reaction is not particularly limited in the presentinvention and may be carried out under conditions in which thehalogen-metal bond reaction can be made sufficiently.

The reaction may be carried out at the reflux temperature of thesolvent, for example, at 50 to 250° C. for 0.5 to 5 hours, preferablyfor 1 to 3 hours.

At this time, the solvent may be any solvent capable of sufficientlydissolving the compounds of Formulas 2 and 3, and for example, may beany one selected from the group consisting of N,N-dimethylformamide(DMF), tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), acetonitrile,dioxane, benzene, toluene, ether, methanol, hexane, cyclohexane,pyridine, N-methyl pyrrolidone, and combinations thereof, and maypreferably be DMF.

After the reaction, a high-purity compound may be obtained through apost-treatment such as ordinary washing, drying, purifying and the likeafter the solvent is distilled.

The hydroxyl pyranone compound of Formula 1 according to the presentinvention can be applied to various fields and may preferably be used incosmetic compositions as an active ingredient. At this time, thecompound of Formula 1 promotes adipocyte differentiation, and thus lipiddroplets can be generated and accumulated, thereby improving wrinklesand elasticity of the skin

When the hydroxyl pyranone compound is used in a cosmetic composition asan active ingredient, the content thereof varies depending on theformulation and may be used in an amount of from 0.001 to 99% by weight.When the active ingredient is contained in the above range, it is notonly suitable for exhibiting the intended effect of the presentinvention but also can satisfy both the stability and solubility of thecomposition, and it can be most efficient in terms ofcost-effectiveness.

The cosmetic composition may be prepared in any of the formulationsconventionally manufactured in the prior art and may be formulated as,for example, but not limited to, solution, suspension, emulsion, paste,gel, cream, lotion, powder, oil, powder foundation, emulsion foundation,wax foundation and spray. More specifically, the cosmetic compositionmay be prepared as a formulation of sun cream, softening lotion,astringent lotion, nutrient lotion, nutrient cream, massage cream,essence, eye cream, pack, spray or powder.

In addition, the cosmetic composition according to the present inventionmay include fats, organic solvents, solubilizer, thickeners, gellingagents, softeners, antioxidants, suspending agents, stabilizers, foamingagents, perfumes, surfactants, water, ionic or non-ionic emulsifiers,fillers, metal ion sequestrants and chelators, preservatives, vitamins,screening agents, humectants, essential oils, dyes, pigments,hydrophilic or lipophilic activating agents and lipid vesicles oradditives commonly used in the field of cosmetics or dermatology, suchas any other component commonly used in cosmetics. Thw additives may beintroduced in amounts commonly used in the field of cosmetics ordermatology.

When the formulation is a paste, a cream or a gel, animal oils,vegetable oils, wax, paraffin, starch, tragacanth, cellulose derivative,polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide,etc. may be used as a carrier component.

When the formulation is a powder or a spray, lactose, talc, silica,aluminum hydroxide, calcium silicate or polyamide powder may be used asa carrier component. In particular, the spray may additionally comprisepropellants such as chlorofluorohydrocarbon, propane/butane or dimethylether.

When the formulation is a solution or an emulsion, solvent, solubilizingagents or emulsifying agents may be used as a carrier component. Forexample, water, ethanol, isopropanol, ethyl carbonate, ethyl acetate,benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil,glycerol aliphatic ester, polyethylene glycol or a fatty acid ester ofsorbitan may be used.

When the formulation is a suspension, liquid diluents such as water,ethanol or propylene glycol, suspending agents such as ethoxylatedisostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylenesorbitan ester, or microcrystalline cellulose, aluminum metahydroxide,bentonite, agar, tragacanth, etc. may be used as a carrier component.

Hereinafter, examples and test examples are provided for furtherexplanation of the contents and effects of the present invention.However, the following contents are only examples of the presentinvention, and the scope and effect of the present invention are notlimited thereto.

EXAMPLE Preparation of 3-(2,6,6-trimethyl-cyclohex-1-enyl)-propenoicacid 5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester

3-(2,6,6-trimethyl-cyclohex-1-enyl)-propenoic acid5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester which is the hydroxyl pyranonecompound of Formula 1 of the present invention was prepared according tothe following Reaction Scheme 2.

The detailed procedure for carrying out the Reaction Scheme 2 was asfollows.

50 g of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (0.35 mmol) wasdissolved in 250 ml of N,N-dimethylformamide and cooled in an iced waterbath at 10° C. and then 50 g (0.42 mol) of thionyl chloride was addeddropwise over 30 minutes. After stirring at room temperature for 2hours, the reaction solution was added to 2000 ml of an iced water. Theresulting solid was filtered, and the solid (filtered material) wasdissolved in 1000 ml of ethyl acetate. Magnesium sulfate and activatedcharcoal were added thereto for drying and decolorization and werefiltered, and then the filtrate was concentrated and nucleic acid wasadded to obtain crystals. The resulting crystals were dried under vacuumto obtain 39.5 g (70%) of the reaction product,5-hydroxy-2-(chloromethyl)-4H-pyran-4-one of the Formula 2-1 as a yellowsolid.

Subsequently, 5 g (0.026 mol) of3-(2,6,6-timethyl-cyclohex-1-enyl)-propenoic acid and 1.3 g (0.031 mol)of sodium hydroxide were dissolved in 40 ml of methanol. After themethanol was distilled off, the remaining residue was dissolved in 70 mlof N,N-dimethylformamide to prepare a compound of Formula 3-1.

To the compound of Formula 3-1, 4.2 g (0.026 mol) of5-hydroxy-2-(chloromethyl)-4H-pyran-4-one of the prepared Formula 2-1was added and then heated and stirred in an oil bath at 110° C. for 2hours. The solvent was distilled off and the residue was dissolved in300 ml of ethyl acetate, and then the ethyl acetate solution was washedwith 5% hydrochloric acid and distilled water, and magnesium sulfate andactivated carbon were added to dry and discolor the solution.Subsequently, the insoluble matters were filtered off and the filtratewas evaporated under reduced pressure to give 5.9 g (69% yield) of thereaction product as an off-white solid.

TLC (ethyl acetate: hexane=1:1) Rf=0.43

¹H NMR (DMSO-d₆, δ): 9.23(s, 1H), 8.09(s, 1H), 7.45(d, 1H, J=16.2Hz),6.48(s, 1H), 5.94(d, 1H, J=16.2Hz), 5.04(s, 2H), 2.07(m, 2H), 1.75(s,3H), 1.59(m, 2H), 1.42(m, 2H), 1.04(s, 6H)

TEST EXAMPLE Confirmation of Adipocyte Differentiation Promoting Effect

In order to examine the adipocyte differentiation promoting effect ofthe compounds prepared in the Example, the following test was carriedout.

Adiponectin is a typical protein hormone secreted from adipocytes. Ithas been reported that as adipocytes are differentiated, the expressionof adiponectin is increased. Therefore, the adipocyte differentiationpromoting effect was confirmed by measuring the amount of adiponectinexpressed in the cell culture medium when treated with the novelcompound of the present invention, which is an indicator of adipocytedifferentiation promoting.

The adipocyte differentiation was performed by culturing human adiposetissue derived mesenchymal stem cells (hAT-MSCs) from Lonza Inc.(Walkersville, Md., USA) according to Lonza's guidelines. The adipocytedifferentiation was carried out using the method recommended by LonzaInc., except that the adipocyte differentiation of adipose-derivedmesenchymal stem cells is induced by using troglitazone (TRO) instead ofindomethacin. Specifically, the mesenchymal stem cells weredifferentiated into adipocytes by adding the medium for adipocytedifferentiation (hereinafter referred to as IDX), which was prepared bymixing 1 g/ml of insulin, 1 M of Dexamethasone (DEXA), 0.5 mM ofisobutylmethylxanthine (IBMX) and 2 M of TRO, to the culture medium ofmesenchymal stem cells, and then culturing it.

In order to determine the expression level of adiponectin, after themedium for adipocyte differentiation was collected on the 14th day ofdifferentiation, the amount of adiponectin was quantified using theAdiponectin ELISA Kit (R & D systems, Cat. No. DY1065) (each data valuewas corrected by the control group). The specific measurement methodusing Adiponectin ELISA Kit was as follows.

First, the capture antibody was reacted in a 96-well plate, washed withwashing buffer solution, and then the material shown in Table 1 belowwas added and reacted at room temperature for 2 hours. Thereafter, whilewashing three times every time when going through each step, thedetection antibody, the HRP enzyme, the substrate solution, and the stopsolution were added in order and reacted for the time indicated in theprotocol. After the final reaction, the absorbance was measured at awavelength of 450 nm using a spectrophotometer.

The results obtained through the above process are shown in Table 1.

TABLE 1 Treating material Adiponectin (pg/ml, Avg ± S.D.) Untreatedgroup  31 ± 10 IDX treated group 303 ± 40 IDX + Glibenclamide 1920 ± 100IDX + Kojic acid (400M) 303 ± 98 IDX + Seletinoid G (60M) 1505 ± 109IDX + compound of example 1804 ± 110 (Formula 1) (60M)

Referring to Table 1, when treated with kojic acid in the experiment forconfirming the expression level of adiponectin, the expression level ofadiponectin was not increased. On the other hand, when treated with thehydroxy pyranone derivative of the compound of Formula 1 of Exampleaccording to the present invention, it was confirmed that the expressionlevel increases almost similarly to that with Glibenclamide, which is apositive control group. This corresponds to a significantly increasedexpression level even in comparison with the case of treatment withSeletinoid G, which is a conventional adipocyte differentiationpromoting compound.

Therefore, it was confirmed that the hydroxyl pyranone compound ofFormula 1 according to the present invention has excellent adipocytedifferentiation promoting ability, and the cosmetic compositioncontaining it as an effective component can increase the volume andelasticity of the skin.

Hereinafter, formulation examples of cosmetic compositions according toatill another aspect of the present disclosure are provided. However,the cosmetic formulations comprising the hydroxyl pyranone compoundaccording to the present invention are not limited only to the followingexamples.

FORMULATION EXAMPLE 1 Lotion

A lotion was prepared using the compositions shown in Table 2 belowaccording to a conventional method.

TABLE 2 Component Content (wt. %) Compound of Formula 1 (Example) 0.1Glycerine 3.0 Buthylene glycol 2.0 Propylene glycol 2.0 Carboxyvinylpolymer 0.1 PEG 12 nonylphenyl ether 0.2 Polysorbate 80 0.4 Ethanol 10.0Triethanolamine 0.1 Preservative, Pigment, Perfume q.s. Purified waterremainder

FORMULATION EXAMPLE 2 Milk Lotion

A milk lotion was prepared using the compositions shown in Table 3 belowaccording to a conventional method.

TABLE 3 Combined component Content (wt. %) Compound of Formula 1(Example) 1.0 Glycerine 3.0 Buthylene glycol 3.0 Propylene glycol 3.0Carboxyvinyl polymer 0.1 Bee wax 4.0 Polysorbate 60 1.5 Caprlic/caprictriglyceride 5.0 Squalane 5.0 Sorbitansesquiolate 1.5 Liquid paraffin0.5 Cetearyl alcohol 1.0 Triethanolamine 0.2 Preservative, Pigment,Perfume q.s. Purified water remainder

FORMULATION EXAMPLE 3 Nutrient Cream

A nutrient cream was prepared using the compositions shown in Table 4below according to a conventional method.

TABLE 4 Component Content (wt. %) Compound of Formula 1 (Example) 2.0Polysorbate 60 1.5 Sorbitansesquiolate 0.5 PEG 60 hydrogenated castoroil 2.0 Liquid paraffin 10. Squalane 5.0 Caprlic/capric triglyceride 5.0Glycerine 5.0 Buthylene glycol 3.0 Propylene glycol 3.0 Triethanolamine0.2 Preservative, Pigment, Perfume q.s. Purified water remainder

FORMULATION EXAMPLE 4 Massage Cream

A massage cream was prepared using the compositions shown in Table 5below according to a conventional method.

TABLE 5 Component Content (wt. %) Compound of Formula 1 (Example) 1.0Bee wax 10.0 Polysorbate 60 1.5 PEG 60 hydrogenated castor oil 2.0Sorbitansesquiolate 0.8 Liquid paraffin 40.0 Squalane 5.0 Caprlic/caprictriglyceride 4.0 Glycerine 5.0 Buthylene glycol 3.0 Propylene glycol 3.0Triethanolamine 0.2 Preservative, Pigment, Perfume q.s. Purified waterremainder

FORMULATION EXAMPLE 5 Pack

A pack was prepared using the compositions shown in Table 6 belowaccording to a conventional method.

TABLE 6 Component Content (wt. %) Compound of Formula 1 (Example) 0.2Polyvinyl alcohol 13.0 Sodium carboxymethyl cellulose 0.2 Glycerine 5.0Allantoin 0.1 Ethanol 6.0 PEG 12 nonylphenyl ether 0.3 Polysorbate 600.3 Preservative, Pigment, Perfume q.s. Purified water remainder

1. A hydroxyl pyranone compound represented by the following Formula 1:


2. A method for preparing a hydroxyl pyranone compound of Formula 1 byreacting a pyranone compound of Formula 2 and a cyclohexenyl estercompound of Formula 3, which is represented by the following ReactionScheme 1:

wherein X is a halogen element and M is Li, Na or K.
 3. A cosmeticcomposition comprising a hydroxyl pyranone compound represented by thefollowing Formula 1 as an active ingredient:


4. The cosmetic composition of claim 3, wherein the cosmetic compositionhas adipocyte differentiation promoting ability.